A phase 1, first-in-human study of IK-930, an oral TEAD inhibitor targeting the Hippo pathway in subjects with advanced solid tumors.
Authors: Anthony W. Tolcher, Nehal J. Lakhani, Meredith McKean, Trupti Lingaraj, Laura Victor, Marta Sanchez-Martin, Katherine Kacena, Karim S. Malek, Sergio Santillana
Journal: Journal of Clinical Oncology (2022)

TPS3168 Background: The transcriptional enhanced associate domain (TEAD) family of proteins are key transcription factors in the Hippo signaling pathway and play a critical role in cell proliferation, migration, angiogenesis, and apoptosis. Published literature demonstrates that approximately 10% of all solid tumors present with a dysregulated Hippo pathway and subsequent constitutive activation of TEAD, which drives gene expression involved in cell growth and pro-survival signaling. Deficiencies in neurofibromin 2 (NF2), a key regulator of the Hippo pathway, can be found in over 40% of cases of malignant pleural mesothelioma (MPM). NF2 deficiency also occurs at high incidence in meningiomas, cholangiocarcinomas, thymoma, and schwannoma. Gene fusions in in Yes1 associated transcriptional regulator (YAP1) or WW domain containing transcription regulator 1 (TAZ/WWTR1) are also indicative of high TEAD activation and can be seen in solid tumors including epithelioid hemangioendothelioma (EHE) where &gt;90% of cases are associated with TAZ-CAMTA1 gene fusion and the other 10% of cases have YAP1/TFE3 gene fusion. IK-930 is a novel, selective, small molecule inhibitor of TEAD that prevents palmitate binding and thereby disrupts aberrant TEAD-dependent transcription. In preclinical models, IK-930 demonstrates antitumor activity in mouse xenograft models with Hippo pathway genetic alterations. IK-930 is under clinical investigation as an oral agent in patients with advanced solid tumors. Methods: This is a phase 1, first-in-human, open-label, multicenter dose escalation and dose expansion study to evaluate the safety and tolerability of IK-930 as monotherapy, and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) using the Bayesian Optimal Interval Design (BOIN). Eligible participants in dose escalation include adult patients with advanced or metastatic solid tumors for whom there is no available therapy known to confer clinical benefit. Patients will receive escalating doses of IK-930 starting at 25mg daily. IK-930 will be administered initially in a 28-day cycle and will progress to a 21-day cycle when evaluated as safe and well-tolerated. A dose expansion phase will follow with four genetically defined cohorts of solid tumors, including: NF2-deficient MPM (Cohort 1), other NF2-deficient solid tumors agnostic to tumor type (Cohort 2), EHE with TAZ-CAMTA1 or YAP1-TFE3 gene fusions (Cohort3), and solid tumors with YAP1/TAZ gene fusions agnostic to tumor type (Cohort 4). Primary endpoints include evaluation of dose-limiting toxicities and treatment-emergent adverse events and determination of RP2D and/or MTD. Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1 and pharmacokinetic (PK) parameters. The study began in January 2022 and is currently enrolling. Clinical trial information: NCT05228015.